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Niacin (nicotinic acid, NA) is administered orally as an antihyperlipidemic agent in extended-release (ER) tablets in high doses. Due to rapid absorption and extensive metabolism (non-linear pharmacokinetics), the drug plasma levels are highly variable, which may correlate with side effects. Interestingly, this erratic drug delivery behavior of niacin ER products cannot be clarified by compendial in vitro release testing. The standard dissolution tests do not allow to mimic the selected GI tract characteristics in order to estimate the robustness of formulation under the variability of the physiological conditions. These are characterized by the pH value, impact of motility forces and composition, as well as volume of GI liquids. Our paper demonstrates a comparison of a newly developed ER HPMC niacin formulation with an originator product. The research aimed to design a robust matrix tablet of comparable biopharmaceutical behavior, safety and efficacy. The extensive in vitro investigation, including dynamic studies in flow-through cell apparatus and stress test device, forms the basis for the evaluation of nicotinic acid plasma concentrations in vivo. The occurrence of erratic, multiple NA plasma peaks after the administration of both extendedrelease products is a result of its local input excess over the metabolic threshold (at the level corresponding to maximum 2% of the administered dose, i.e., 20 mg of drug) due to the mechanical stresses of physiological intensity. We demonstrate how this behavior is similar for both marketed and test products. In this context, we describe how a robust ER matrix and well-designed formulation does not guarantee the test product's bioequivalence to the comparator one out of reasons unrelated to technology and biopharmaceutical properties, but because of the active compound's intrinsic pharmacokinetic characteristics, i.e., highly variable, extensive metabolism of nicotinic acid.